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PR3-ANCA in Wegener's granulomatosis prime human mononuclear cells for enhanced activation via TLRs and NOD1/2

DOI: 10.1186/1746-1596-4-23

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Abstract:

In this study, we examined whether PR3-ANCA sera and purified immunoglobulins from patients with Wegener's granulomatosis prime human monocytic cells for enhanced responses to microbial components in terms of production of proinflammatory cytokines.Flow cytometry demonstrated that stimulation with antibodies to proteinase 3 enhanced the expression of TLR2, 3, 4, 7, and 9, NOD1, and NOD2 in human mononuclear cells. The sera and purified immunoglobulins significantly primed human mononuclear cells to secrete interleukin-8 in response to microbial components via TLRs and NODs. Priming effects were also observed for the production of interleukin-6, monocyte chemoattractant protein-1, and tumor necrosis factor-α. On the other hand, PR3-ANCA-negative sera from patients with polyarteritis nodosa which possibly related to MPO-ANCA and aortitis syndrome as well as control sera from a healthy volunteer did not have any priming effects on PBMCs.In conclusion, PR3-ANCA prime human mononuclear cells to produce cytokines upon stimulation with various microbial components by up-regulating the TLR and NOD signaling pathway, and these mechanisms may partially participate in the inflammatory process in Wegener's granulomatosis.Anti-neutrophil cytoplasmic antibodies (ANCA) form a heterogeneous group of Abs that target antigens present mostly in azurophilic granules of polymorphonuclear leukocytes. ANCA were first discovered in the 1970s, when cytoplasmic fluorescence was observed during investigations of anti-nuclear antibodies (Abs) by indirect fluorescence on human granulocytes [1]. In the 1980s, the spectrum of diseases associated with ANCA became clearer, and vasculitis [2,3] was identified as a common sign of these diseases. A connection between ANCA and Wegener's granulomatosis (WG) was established [4].ANCA are directed against antigens located in the cytoplasmic space of polymorphonuclear leukocytes and monocytes. Two of the main targets have been identified as enzymes, both pa

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